Unsaturated aldehydes (enals) are the major end products generated during the oxidation of biological membranes and lipids. These compounds are also present in the environment and industrial pollutants, and are generated during the metabolism of several foods and drugs. In vitro, enals are highly toxic, however, there contribution to oxidative injury and the pathophysiological consequences of lipid peroxidation has not been assessed. Our previous work has led to the identification of the major biochemical pathways that metabolize enals in the heart and other cardiovascular tissues. Our studies show that the enzyme aldose reductase (AR) plays a central role in the cardiovascular toxicity of enals. We find that inhibition of AR abolishes ischemic preconditioning of the heart and increases the accumulation of the prototypical enal - 4-hydroxy trans-2-nonenal (HNE) during myocardial ischemia and reperfusion (I/R). Based on these observations, we propose that enals derived from lipid peroxidation are a significant cause of myocardial ischemic injury. To test this hypothesis, we plan to examine how enals are metabolized in the ischemic heart (Aim 1) and whether ischemic changes in cofactor availability and metabolite extrusion compromise enal detoxification. Using isolated perfused hearts subjected to global ischemia and a conscious rabbit model of regional ischemia in situ, we will examine the generation of enals and their metabolites during I/R. Developing on our previous observations, we will investigate the role of AR in enal metabolism during I/R, and delineate its contribution to enal detoxification in ischemic hearts (Aim2). Finally, we will examine how ischemic preconditioning causes long-term changes in enal metabolism and how the aerobic and ischemic preconditioned hearts metabolize and detoxifies enals (Aim 3). The results of these investigations will result in a better understanding of the mechanisms by which lipid peroxidation contributes to ischemic injury and to the elucidation of the role of enals and their metabolic pathways in the development of ischemic injury and dysfunction. Outcomes of this project could form the basis of future studies for assessing individual variations in susceptibility to ischemia and for understanding a host of pathological states associated with enal toxicity or exposure.